The potentially deleterious effects of stress on health have long been recognized. As the basic mechanisms of interplay among elements of neurobiology, endocrinology, immunology and behavior are becoming appreciated, the relationship of stressful stimulation to these disorders is becoming accessible to study. One of the major pathways for the expression of the stress response of the endocrine system involves the release of corticotropin-releasing factor (CRF) from the hypothalamus and the subsequent release of ACTH from the pituitary. There is now reason to believe that CRF may also have a role in regulating other manifestations of the stress response such as sympathetic nervous system activation and the initiation of behavioral responses such as decreased appetite, expression of displacement behavior and an exaggerated startle response. A 41-amino acid peptide CRF was structurally identifed on the basis of its ability to release pituitary ACTH and beta-endorphin both in vitro and in vivo. CRF-immunoreactive fibers and cell bodies are found in a variety of sites in the CNS and this distribution roughly parallels that of high affinity, specific binding sites. CRF has been shown to alter CNS neuronal firing rates both in vivo and in vitro. If administered into the lateral cerebral ventricles (icv), CRF produces two other effects also associated with stress-activation of the sympathetic nervous system and an enhanced behavioral response to novelty stress. These effects appear to be independent of any action at the pituitary. (references in body of proposal) The goal of the proposed research is to better define the scope of the behavioral effects of icv CRF and explore the ways in which CRF might be involved in mediating stress-related behavior. We will use two different behavioral tests: a modified open field test and a potentiated acoustic startle response. We will first determine if the behavioral effects of icv CRF in either setting are related to an activation of the pituitary or sympathetic nervous system. If no such relationship can be found we will use a variety of pharmacological approaches to attempt to define the biochemical nature of the CRF effects on behavior. This will include the use of CRF antagonist to study possible involvement of endogenous CRF in stress-related behavior.